Prevalence of surgical site infections after open reduction and internal fixation for mandibular fractures: a systematic review and meta-analysis

Our study aims to estimate the prevalence of surgical site infections (SSI) following open reduction and internal fixation (ORIF) for mandibular fractures and to determine the effect of potential moderators on it. A systematic literature search (Medline and Scopus databases) was conducted independently by two reviewers. The pooled prevalence with 95% confidence intervals was estimated. Quality assessment as well as outlier and influential analysis were performed. Additionally, subgroup and meta-regression analysis were conducted in order the effect of categorical and continuous variables on the estimated prevalence to be investigated. In total, seventy-five eligible studies (comprising a sum of 5825 participants) were included in this meta-analysis. The overall prevalence of SSI following ORIF for mandibular fractures was estimated as high as 4.2% (95% CI 3.0–5.6%) with significant heterogeneity between studies. One study was identified to be critically influential. In the subgroup analysis, the prevalence was 4.2% (95% CI 2.2–6.6%) among studies conducted in Europe, 4.3% (95% CI 3.1–5.6%) among studies conducted in Asia and higher among those conducted in America (7.3%) (95% CI 4.7–10.3%). It is important for healthcare professionals to be aware of the etiology of these infections, despite the relatively low rate of SSI in these procedures. However, further, well-designed prospective and retrospective studies need to be conducted in order this issue to be fully clarified.

www.nature.com/scientificreports/ reports, case series with less than ten participants, review articles, randomized clinical trials 20,21 , animals studies, letters to the editor, books, expert opinion, conference abstracts, studies with no full-text available, studies not written in English, articles without adequate (at least one month postoperative) or unspecified follow-up period [22][23][24][25][26][27][28] , studies regarding pediatric population 17,29 , studies conducting in Africa 30 , articles with unspecified type of infection, studies regarding non mandibular fractures 31 , studies regarding solely SSI in population with comorbidities (e.g. diabetes melitus, autoimmune diseases), articles containing data derived from surveillance databases and articles investigating postoperative infections per fracture [32][33][34][35] were excluded. In articles with overlapping populations, the most recent or most complete publication was considered eligible. The following variables were obtained from each study: the first author's name, year of publication, study design, continent of origin, study period, total patients, fractures patients ratio, proportion of males, mean age, and patients with postoperative infections.
Quality assessment. Quality appraisal was independently performed by two investigators using the National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment Tools. The NHLBI quality assessment tool for Observational Cohort and Cross-Sectional Studies was employed. Each study was assessed for potential flaws in accordance the methodology or the implementation of each survey that could jeopardize internal validity. For each of the fourteen questions, investigators could select one of the following answers: "yes", "no", "cannot determine" (e.g., data were unclear or contradictory) or "not reported" (e.g., missed data) or "not applicable" (e.g., not relevant question regarding this type of study). Study quality was defined as "low", "moderate" or "high" risk of bias 36 .
Statistical analysis. Statistical analysis was carried out using RStudio (version: 2022.12.0 + 353) software (RStudio Team 37 . The meta-analysis was conducted through metafor package 38 . The DerSimonian and Laird random-effects model was used to estimate the pooled prevalence and its respective 95% confidence intervals (CI). Freeman-Tukey double arscine transformation was performed 39 . Heterogeneity presence between studies was evaluated through visual inspection of the forest plot and by using the Cochran's Q statistic and its respective p value. The Higgins I 2 statistic and its respective 95% CI were used for quantifying the magnitude of true heterogeneity in effect sizes. An I 2 value of 0-40%, 30-60%, 50-60% and 75-100% indicated not important, moderate, substantial and considerable heterogeneity, respectively. To determine if the potential outlying effect sizes were also influential, screening for externally studentized residuals with z-values larger than two in absolute value and leave-one-out diagnostics were performed 40 . Due to high heterogeneity remaining, subgroup and meta-regression analysis were performed. In the conducted subgroup analysis, the continent of origin was chosen as the categorical moderator on effect sizes. In the performed meta-regression analysis with continuous variables, the year of publication, the proportion of males and the mean age were assessed as moderators on effect sizes. Due to paucity of data (less than ten studies for each covariate) regarding the smoking status and other variables (e.g., duration of surgery, alcohol, obesity, surgeon level), these data were not included in this analysis 41 . Unless otherwise stipulated, the statistical significance was established at p = 0.05 (two-tailed). Tests to evaluate publication bias, such as Egger's test 42 , Begg's test 43 and funnel plots, were developed in the context of comparative data. They assume studies with positive results are more frequently published than studies with negative results, however in a meta-analysis of proportions there is no clear definition or consensus about what a positive result is 44 . Therefore, publication bias in this current meta-analysis was assessed qualitatively.

Results
Results and characteristics of the included studies. In total, seventy-five studies (comprising a sum of 5825 participants) were finally included in this analysis. The descriptive characteristics of them are reported in Table 1. All articles were published from 1989 to 2022 (conducted from 1980 to 2020). Eighteen of them were of cohort design and the remaining ones of cross-sectional. Most of the studies were carried out in Asia, followed by America and Europe. The average percentage of males was 83.4% and the mean age of participants ranged from 22.4 to 42 years (median: 29.7 years). As per the quality assessment, eight studies were estimated as high quality 6,7,46,48,52,85,92,102 and the remaining ones, as moderate (Supplementary materials, Supplementary Table 2).

Subgroup and meta-regression analysis. The forest plot of the subgroup analysis is illustrated in Sup-
plementary material ( Supplementary Fig. 3). The prevalence was 4.2% (95% CI 2.2-6.6%) among studies conducted in Europe, 4.3% (95% CI 3.1-5.6%) among studies conducted in Asia and higher among those conducted in America (7.3%) (95% CI 4.7-10.3%). Heterogeneity remained high in studies conducted in America and moderate in those conducted Europe and low among those conducted in Asia. According to the results of the test for subgroup differences a statistically significant finding was noted. In the meta-regression analysis with continuous variables, a statistically significant negative association between age and the odds of SSI after ORIF for mandibular fractures was observed, as illustrated in Supplementary material (Supplementary Table 1).

Discussion
To the best of our knowledge this is the first attempt to evaluate the prevalence of SSI after ORIF for mandibular fractures through a systematic review. Therefore, there are no published data available to compare our estimate with. According to the results of this study, the prevalence of SSI following ORIF for mandibular fractures is estimated at 4.2% (95%CI 3.0%-5.6%) with substantial heterogeneity. The subjectivity of the SSI's diagnosis among medical doctors, the type of surgery and other potential risk factors such as diabetes, prolonged operative time, obesity, patients' age, gender, additional procedures, smoking status, alcohol consumption, oral hygiene, perioperative warming and the lack of defined guidelines regarding the antibiotic protocol use may influence the prevalence of SSI following ORIF for mandibular fractures [114][115][116][117][118][119] . Moreover, significant heterogeneity is expected in prevalence and incidence estimates due to the type of this study (differences in the time and place where included studies were conducted). Therefore, high I 2 in the context of proportional meta-analysis does not necessarily mean that data is inconsistent 44 . In the subgroup analysis, this prevalence varied by the continent of study's origin, ranging from 4.2% (95% CI 2.2-6.6%) among European studies, to 7.3% (95% CI 4.7-10.3%) among American and 4.3% (95% CI 3.1-5.6%) among Asian ones. Regarding the statistically significant difference in subgroup analysis, due to lack of data, it was not possible to determine the factors associated with it. It is worth emphasizing again that the current studies are observational and have been conducted in different locations, times, and conditions. Additionally, the pathogens that can contaminate surgical wounds, the surgical practices or even the antibiotics used may vary from country to country. Similar, reduction in the prevalence of SSI was found in a recent meta-analysis 120 . However, this study does not provide a comprehensive representation since it utilizes data from multiple and in many cases unidentified surgical procedures. Regarding the influence of the age in meta-regression analysis, it should be noted that, on the one hand, the mean ages range from 22.4 to 42 years, which means that the majority of the patient related comorbidities (e.g., type 2 diabetes, which occurs above the age of 45 121 ) commonly associated with aging are likely in their early stages or have not yet become evident, thereby implying that their potential influence on surgical outcomes remains limited. On the other hand, it is important to recognize that this result could be influenced by various confounding factors that require further investigation. According to WHO in low-and middle-income countries, one out of ten patients (11.8%) develop an SSI after a surgical procedure 122 . ORIF for mandibular fractures can be consider a safe surgical procedure, regardless of the specific nature of this operation. In most SSI, the responsible pathogens originate from the patient's endogenous flora. The oral cavity consists of a unique environment coated with a plethora of bacteria, which form the bacterial biofilm. The oral microbiome can be categorized into two types: the core microbiome, which is common to all individuals and the variable microbiome, which is unique to individuals based on their lifestyle and physiological differences. The normal microbiome is formed by bacteria, fungi, viruses, archaea and protozoa. Among them, the most commonly isolated bacteria are Gram positive Cocci (e.g. Streptococcus, Peptostreptococcus), Gram positive Rods (e.g. Actinomyces, Lactobacillus), Gram negative Cocci (e.g. Moraxella, Veillonella), Gram negative www.nature.com/scientificreports/ Rods (e.g. Campylobacter, Fusobacterium) 123 . These bacteria are capable of contaminating oral wounds. In terms of the treatment used for mandibular fractures, Jazayeri et al. 124 analyzed data from nine studies (involving 667 patients) found that ORIF is associated with a higher incidence of postoperative infection (relative risk, 3.6; 95% CI 3.9 to 13.8) compared to closed reduction. Regarding the plate and screw system (locking or nonlocking) used, Zhan et al. 125  www.nature.com/scientificreports/ author based on the available retrospective studies found out that tooth extraction (which located in line of the fracture) during ORIF procedures was not associated with increased risk of SSI. Even if the prevalence of SSI may be considered low, SSI still remains one of the most frequent types of health care-associated infections. In order the impact of SSI to be minimized, it is mandatory that necessary preventive measures such as, screening for colonization, isolation of patients with multidrug resistant bacteria, decolonization, surgical site preparation, surgical hand preparation, wearing sterile protective equipment and hygiene and aseptic techniques to be followed 122,127 . To date, there is no consensus regarding the antibiotic regimen used; hence, specific guidelines in country level should be implemented by global organizations, in order inappropriate antibiotic prescribing and the devastating consequences of it, to be avoided. The excess prescription of broadspectrum chemoprophylaxis leads to antimicrobial resistance, which poses a major threat to public health by increasing mortality around the world, especially in low resources settings. According to a recent systematic review regarding the antibiotics prophylaxis in maxillofacial trauma, preoperative antibiotics were related with lower infection rates while prolonged antibiotic regimens showed no significant benefit 128 . Moreover, de Jonge et al. 129 combining data from fourteen studies (54,552 participants) found out that the administration of antibiotic prophylaxis for more than 120 min prior to the first incision or after the inception of the surgical procedure was associated with higher risk of SSI than administration less than 120 min. Tetanus prophylaxis should also be considered in open mandibular fractures. Pain control should be achieved with acetaminophen, NSAIDs, and/ or opioids. Steroids and ice packs are useful for reducing edema 3 . It is important for healthcare professionals to be aware of the etiology of these infections. Consequently, it is imperative to conduct both prospective and retrospective studies, including observational and interventional approaches, to thoroughly investigate the correlation between SSI following ORIF for mandibular fractures and potential risk factors.

Study's strengths and limitations.
The main strength of the current study was the comprehensive methodology applied for the literature search, study selection, inclusion/exclusion criteria, screening for eligibility, quality assessment and pooling analysis of prevalence data from forty studies. However, the present study had several limitations. It should be noted that the unidentified heterogeneity remained substantial, therefore, the results should be interpreted with caution. The highly heterogenous outcomes across the included studies were expected due to the nature of this type of studies. The subjectivity of the SSI's diagnosis among medical doctors and other potential risk factors such as diabetes, prolonged operative time, obesity, patients' age, gender, additional procedures performed, smoking status, alcohol consumption, oral hygiene, perioperative warming, the type of surgery and the lack of defined guidelines regarding the antibiotic protocol used might bias the prevalence of SSI following ORIF for mandibular fractures. Due to limited data (less than ten studies for each covariate) regarding variables such as smoking status, duration of surgery, alcohol, obesity, surgeon level, these variables were excluded from this presented analysis. Moreover, only observational studies written in English language were included resulting in the occurrence of reporting bias. Consequently, the existing evidence may be constrained and lacking comprehensive representation due to the omission of studies composed in languages other than English (e.g. studies carried out and documented in countries where English is not the primary language and which possess limited resources). Only studies from Europe, America, and Asia were finally included in our analysis. Therefore, it is important to note again that the results should be interpreted cautiously due to the limited generalizability of the data and the potential underestimation or overestimation of the prevalence.

Data availability
Literature and Rstudio data are available from the corresponding author on reasonable request. www.nature.com/scientificreports/